Garrett R.H., Grisham C.M. - Biochemistry (1999)(2nd ed.)(en)

8.1 ● Fatty Acids

241

A D E E P E R L O O K

Fatty Acids in Food: Saturated Versus Unsaturated

Fats consumed in the modern human diet vary widely in their fatty acid compositions. The table below provides a brief summary. The incidence of cardiovascular disease is correlated with diets high in saturated fatty acids. By contrast, a diet that is relatively higher in unsaturated fatty acids (especially polyunsaturated fatty acids) may reduce the risk of heart attacks and strokes. Corn oil, abundant in the United States and high in (polyunsaturated) linoleic acid, is an attractive dietary choice. Margarine made from corn, safflower, or sunflower oils is much lower in saturated fatty acids than is butter, which is made from milk fat. However, margarine may present its own health risks. Its fatty acids contain trans-double bonds (introduced by the hydrogenation process), which may also contribute to cardiovascular disease. (Margarine was invented by a French chemist, H. Mège Mouriès, who won a prize from Napoleon III in 1869 for developing a substitute for butter.)

Although vegetable oils usually contain a higher proportion of unsaturated fatty acids than do animal oils and fats, several plant oils are actually high in saturated fats. Palm oil is low in polyunsaturated fatty acids and particularly high in (saturated) palmitic acid (whence the name palmitic). Coconut oil is particularly high in lauric and myristic acids (both saturated) and contains very few unsaturated fatty acids.

Some of the fatty acids found in the diets of developed nations (often 1 to 10 g of daily fatty acid intake) are trans fatty acids— fatty acids with one or more double bonds in the trans configuration. Some of these derive from dairy fat and ruminant meats, but the bulk are provided by partially hydrogenated vegetable or fish

oils. Substantial evidence now exists to indicate that trans fatty acids may have deleterious health consequences. Numerous studies have shown that trans fatty acids raise plasma LDL cholesterol levels when exchanged for cis-unsaturated fatty acids in the diet and may also lower HDL cholesterol levels and raise triglyceride levels. The effects of trans fatty acids on LDL, HDL, and cholesterol levels are similar to those of saturated fatty acids, and diets aimed at reducing the risk of coronary heart disease should be low in both trans and saturated fatty acids.

H	H
C	C
		O
Oleic acid		C
cis double bond		OH

H

	O
	C
H	OH

Elaidic acid trans double bond

Structure of cis and trans monounsaturated C18 fatty acids.

Fatty Acid Compositions of Some Dietary Lipids*

Source	Lauric and Myristic	Palmitic	Stearic	Oleic	Linoleic
Beef	5	24–32	20–25	37–43	2–3
Milk		25	12	33	3
Coconut	74	10	2	7	—
Corn		8–12	3–4	19–49	34–62
Olive		9	2	84	4
Palm		39	4	40	8
Safflower		6	3	13	78
Soybean		9	6	20	52
Sunflower		6	1	21	66

Data from Merck Index, 10th ed. Rahway, NJ: Merck and Co.; and Wilson, et al., 1967, Principles of Nutrition, 2nd ed. New York: Wiley.

*Values are percentages of total fatty acids.

242 Chapter 8 ● Lipids

Lactobacillic acid

CH3(CH2)5HC CH(CH2)9COOH

CH2

Tuberculostearic acid

CH3(CH2)7CH(CH2)8COOH

CH3

FIGURE 8.2 ● Structures of two unusual fatty acids: lactobacillic acid, a fatty acid containing a cyclopropane ring, and tuberculostearic acid, a branched-chain fatty acid.

prostaglandins, a class of compounds that exert hormone-like effects in many physiological processes (discussed in Chapter 25).

In addition to unsaturated fatty acids, several other modified fatty acids are found in nature. Microorganisms, for example, often contain branched-chain fatty acids, such as tuberculostearic acid (Figure 8.2). When these fatty acids are incorporated in membranes, the methyl group constitutes a local structural perturbation in a manner similar to the double bonds in unsaturated fatty acids (see Chapter 9). Some bacteria also synthesize fatty acids containing cyclic structures such as cyclopropane, cyclopropene, and even cyclopentane rings.

8.2 ● Triacylglycerols

A significant number of the fatty acids in plants and animals exist in the form of triacylglycerols (also called triglycerides). Triacylglycerols are a major energy reserve and the principal neutral derivatives of glycerol found in animals. These molecules consist of a glycerol esterified with three fatty acids (Figure 8.3). If all three fatty acid groups are the same, the molecule is called a simple triacylglycerol. Examples include tristearoylglycerol (common name tristearin) and trioleoylglycerol (triolein). Mixed triacylglycerols contain two or three different fatty acids. Triacylglycerols in animals are found primarily in the adipose tissue (body fat), which serves as a depot or storage site for lipids. Monoacylglycerols and diacylglycerols also exist, but are far less common than the triacylglycerols. Most natural plant and animal fat is composed of mixtures of simple and mixed triacylglycerols.

Acylglycerols can be hydrolyzed by heating with acid or base or by treatment with lipases. Hydrolysis with alkali is called saponification and yields salts of free fatty acids and glycerol. This is how soap (a metal salt of an acid derived from fat) was made by our ancestors. One method used potassium hydroxide (potash) leached from wood ashes to hydrolyze animal fat (mostly triacylglycerols). (The tendency of such soaps to be precipitated by Mg2 and Ca2 ions in hard water makes them less useful than modern detergents.) When the fatty acids esterified at the first and third carbons of glycerol are different, the sec-

H2C CH CH2

HO OH OH

Glycerol

H2C

CH

CH2

H2C

CH

CH2

O

O

O

O

O

O

O

C

C

O C

O

O

C

C

O C

O

	Myristic	Palmitoleic
Tristearin	Stearic
(a simple triacylglycerol)	A mixed triacylglycerol

FIGURE 8.3 ● Triacylglycerols are formed from glycerol and fatty acids.

8.3 ● Glycerophospholipids

243

A D E E P E R L O O K

Polar Bears Use Triacylglycerols to Survive Long Periods of Fasting

The polar bear is magnificently adapted to thrive in its harsh Arctic environment. Research by Malcolm Ramsey (at the University of Saskatchewan in Canada) and others has shown that polar bears eat only during a few weeks out of the year and then fast for periods of 8 months or more, consuming no food or water during that time. Eating mainly in the winter, the adult polar bear feeds almost exclusively on seal blubber (largely composed of triacylglycerols), thus building up its own triacylglycerol reserves. Through the Arctic summer, the polar bear maintains normal physical activity, roaming over long distances, but relies entirely on its body fat for sustenance, burning as much as 1 to 1.5 kg of fat per day. It neither urinates nor defecates for extended periods. All the water needed to sustain life is provided from the metabolism of triacylglycerides (because oxidation of fatty acids yields carbon dioxide and water).

Ironically, the word Arctic comes from the ancient Greeks, who understood that the northernmost part of the earth lay under the stars of the constellation Ursa Major, the Great Bear. Although unaware of the polar bear, they called this region Arktikós, which

means “the country of the great bear.”

(Thomas D. Mangelsen/Images of Nature)

ond carbon is asymmetric. The various acylglycerols are normally soluble in benzene, chloroform, ether, and hot ethanol. Although triacylglycerols are insoluble in water, monoand diacylglycerols readily form organized structures in water (discussed later), owing to the polarity of their free hydroxyl groups.

Triacylglycerols are rich in highly reduced carbons and thus yield large amounts of energy in the oxidative reactions of metabolism. Complete oxidation of 1 g of triacylglycerols yields about 38 kJ of energy, whereas proteins and carbohydrates yield only about 17 kJ/g. Also, their hydrophobic nature allows them to aggregate in highly anhydrous forms, whereas polysaccharides and proteins are highly hydrated. For these reasons, triacylglycerols are the molecules of choice for energy storage in animals. Body fat (mainly triacylglycerols) also provides good insulation. Whales and Arctic mammals rely on body fat for both insulation and energy reserves.

8.3 ● Glycerophospholipids

A 1,2-diacylglycerol that has a phosphate group esterified at carbon atom 3 of the glycerol backbone is a glycerophospholipid, also known as a phosphoglyceride or a glycerol phosphatide (Figure 8.4). These lipids form one of the largest classes of natural lipids and one of the most important. They are essential components of cell membranes and are found in small concentrations in other parts of the cell. It should be noted that all glycerophospholipids are members of the broader class of lipids known as phospholipids.

The numbering and nomenclature of glycerophospholipids present a dilemma in that the number 2 carbon of the glycerol backbone of a phos-

244 Chapter 8 ● Lipids

O
C		O
O		CH2
C		O C		H				O
											O–
		CH2				O		P
								O–

FIGURE 8.4 ● Phosphatidic acid, the parent compound for glycerophospholipids.

pholipid is asymmetric. It is possible to name these molecules either as D- or L-isomers. Thus, glycerol phosphate itself can be referred to either as D-glyc- erol-1-phosphate or as L-glycerol-3-phosphate (Figure 8.5). Instead of naming the glycerol phosphatides in this way, biochemists have adopted the stereospecific numbering or sn- system. In this system, the pro-S position of a prochiral atom is denoted as the 1-position, the prochiral atom as the 2-position, and so on. When this scheme is used, the prefix sn- precedes the molecule name (glycerol phosphate in this case) and distinguishes this nomenclature from other approaches. In this way, the glycerol phosphate in natural phosphoglycerides is named sn-glycerol-3-phosphate.

The Most Common Phospholipids

Phosphatidic acid, the parent compound for the glycerol-based phospholipids (Figure 8.4), consists of sn-glycerol-3-phosphate, with fatty acids esterified at the 1- and 2-positions. Phosphatidic acid is found in small amounts in most natural systems and is an important intermediate in the biosynthesis of the more common glycerophospholipids (Figure 8.6). In these compounds, a

A D E E P E R L O O K

Prochirality

If a tetrahedral center in a molecule has two identical substituents, it is referred to as prochiral since, if either of the like substituents is converted to a different group, the tetrahedral center then becomes chiral. Consider glycerol: the central carbon of glycerol is prochiral since replacing either of the OCH2OH groups would make the central carbon chiral. Nomenclature for prochiral centers is based on the (R,S) system (in Chapter 3). To name the otherwise identical substituents of a prochiral center, imagine

increasing slightly the priority of one of them (by substituting a deuterium for a hydrogen, for example) as shown: the resulting molecule has an (S)-configuration about the (now chiral) central carbon atom. The group that contains the deuterium is thus referred to as the pro-S group. As a useful exercise, you should confirm that labeling the other CH2OH group with a deuterium produces the (R)-configuration at the central carbon, so that this latter CH2OH group is the pro-R substituent.

			D
		HOH23C	A
			1CHOH
HOH2C	CH2OH	G D
		2C
G	D	‘	'
C	'	H	OH
‘
H	OH	1-d, 2(S )-Glycerol
Glycerol		(S -configuration at C-2)

pro-S position

CH

OH

CH OPO2–

2

2

3

HO

C

H

H

C

OH

pro-R position

CH2OPO32–

CH2 OH

L-Glycerol-3-phosphate

D-Glycerol-1-phosphate

sn-Glycerol-3-phosphate

O
C	O
O		CH2
C	O	C	H	CH3
			O
		CH2	O P O CH2CH2	N+ CH3
Phosphatidylcholine			O–	CH3

8.3 ● Glycerophospholipids

245

FIGURE 8.5 ● The absolute configuration of sn-glycerol-3-phosphate. The pro-(R) and pro- (S) positions of the parent glycerol are also indicated.

GLYCEROLIPIDS WITH OTHER HEAD GROUPS:

O

+

O

CH2

O

P

O

CH2CH2

NH3

O

P

O

O–

O–

Phosphatidylethanolamine

O

H

C

OH

O

O

COO–

P

O

CH2

O–

O

P

O

CH2

CH

Diphosphatidylglycerol (Cardiolipin)

+

O–

NH3

Phosphatidylserine

H

OH

H

H

OH

H

HO

H

HO

OH

O

O

H

O

CH2

P

O

CH

CH2

O P

O

O–

OH

OH

O–

Phosphatidylglycerol

Phosphatidylinositol

FIGURE 8.6 ● Structures of several glycerophospholipids and space-filling models of phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol.

246 Chapter 8 ● Lipids

variety of polar groups are esterified to the phosphoric acid moiety of the molecule. The phosphate, together with such esterified entities, is referred to as a “head” group. Phosphatides with choline or ethanolamine are referred to as phosphatidylcholine (known commonly as lecithin) or phosphatidylethanolamine, respectively. These phosphatides are two of the most common constituents of biological membranes. Other common head groups found in phosphatides include glycerol, serine, and inositol (Figure 8.6). Another kind of glycerol phosphatide found in many tissues is diphosphatidylglycerol. First observed in heart tissue, it is also called cardiolipin. In cardiolipin, a phosphatidylglycerol is esterified through the C-1 hydroxyl group of the glycerol moiety of the head group to the phosphoryl group of another phosphatidic acid molecule.

A D E E P E R L O O K

Glycerophospholipid Degradation: One of the Effects of Snake Venoms

The venoms of poisonous snakes contain (among other things) a class of enzymes known as phospholipases, enzymes that cause the breakdown of phospholipids. For example, the venoms of the eastern diamondback rattlesnake (Crotalus adamanteus) and the Indian cobra (Naja naja) both contain phospholipase A2, which catalyzes the hydrolysis of fatty acids at the C-2 position of glycerophospholipids.

The phospholipid breakdown product of this reaction, lysolecithin, acts as a detergent and dissolves the membranes of red blood cells, causing them to rupture. Indian cobras kill several thousand people each year.

X

X

O

O

O–

O–

O

P

O

P

O

O

O–

H

H

H2O

+ O

H2C

C CH2

H2C

C CH2

Eastern diamondback rattlesnake. (Dr. E. R.

O

O

O

HO

Degginger)

O

O

O

PLA2

Phospholipid

Indian cobra. (Dr. E. R. Degginger)

FIGURE 8.8

8.3 ● Glycerophospholipids

247

FIGURE 8.7 ● A space-filling model of 1-stearoyl-2-oleoyl-phosphatidylcholine.

Phosphatides exist in many different varieties, depending on the fatty acids esterified to the glycerol group. As we shall see, the nature of the fatty acids can greatly affect the chemical and physical properties of the phosphatides and the membranes that contain them. In most cases, glycerol phosphatides have a saturated fatty acid at position 1 and an unsaturated fatty acid at position 2 of the glycerol. Thus, 1-stearoyl-2-oleoyl-phosphatidylcholine (Figure 8.7) is a common constituent in natural membranes, but 1-linoleoyl-2-palmitoylphos- phatidylcholine is not.

Both structural and functional strategies govern the natural design of the many different kinds of glycerophospholipid head groups and fatty acids. The structural roles of these different glycerophospholipid classes are described in Chapter 9. Certain phospholipids, including phosphatidylinositol and phosphatidylcholine, participate in complex cellular signaling events. These roles, appreciated only in recent years, are described in Chapter 34.

Ether Glycerophospholipids

Ether glycerophospholipids possess an ether linkage instead of an acyl group at the C-1 position of glycerol (Figure 8.8). One of the most versatile biochemical signal molecules found in mammals is platelet activating factor, or PAF, a unique ether glycerophospholipid (Figure 8.9). The alkyl group at C-1 of PAF is typically a 16-carbon chain, but the acyl group at C-2 is a 2-carbon acetate unit. By virtue of this acetate group, PAF is much more water-soluble

O

+

–O P O CH2 CH2 NH3

								O
H2C				CH				CH2
Ether O									Ester
			O
linkage									linkage
R1			C				O
			R2

● A 1-alkyl 2-acyl-phos- phatidylethanolamine (an ether glycerophospholipid).

A D E E P E R L O O K

Platelet Activating Factor: A Potent Glyceroether Mediator

Platelet activating factor (PAF) was first identified by its ability (at low levels) to cause platelet aggregation and dilation of blood vessels, but it is now known to be a potent mediator in inflammation, allergic responses, and shock. PAF effects are observed at tissue concentrations as low as 10 12 M. PAF causes a dramatic inflammation of air passages and induces asthma-like symptoms in laboratory animals. Toxic-shock syndrome occurs when fragments of destroyed bacteria act as toxins and induce the synthesis of PAF. This results in a drop in blood pressure and a reduced

volume of blood pumped by the heart, which leads to shock and, in severe cases, death.

Beneficial effects have also been attributed to PAF. In reproduction, PAF secreted by the fertilized egg is instrumental in the implantation of the egg in the uterine wall. PAF is produced in significant quantities in the lungs of the fetus late in pregnancy and may stimulate the production of fetal lung surfactant, a pro- tein–lipid complex that prevents collapse of the lungs in a newborn infant.

FIGURE 8.9

248 Chapter 8 ● Lipids

O

CH3

–O

+

P

O

CH2

CH2

N

CH3

O

CH3

H2C

CH

CH2

O

O

C

O

Platelet

activating factor

CH3

● The structure of 1-alkyl 2-acetyl-phosphatidylcholine, also known as platelet activating factor or PAF.

than other lipids, allowing PAF to function as a soluble messenger in signal transduction.

Plasmalogens are ether glycerophospholipids in which the alkyl moiety is cis- , -unsaturated (Figure 8.10). Common plasmalogen head groups include choline, ethanolamine, and serine. These lipids are referred to as phosphatidal choline, phosphatidal ethanolamine, and phosphatidal serine.

O

CH3

+

–O

P

O

CH2CH2 N

CH3

Choline plasmalogen

O

CH3

The ethanolamine

CH2

CH

CH2

plasmalogens have

ethanolamine in

H

O

O

place of choline.

C

C

O

C

H

FIGURE 8.10 ● The structure and a space-filling model of a choline plasmalogen.

OH

H

OH

OH

H

OH

H2O

H

C

C

CH2

C

C

CH2

+

H

C

H

NH3

C

H

NH

R

COOH

C

H

Fatty acid

C

C

O

H

R

Sphingosine

Ceramide

8.4 ● Sphingolipids

Sphingolipids represent another class of lipids found frequently in biological membranes. An 18-carbon amino alcohol, sphingosine (Figure 8.11), forms the backbone of these lipids rather than glycerol. Typically, a fatty acid is joined to a sphingosine via an amide linkage to form a ceramide. Sphingomyelins represent a phosphorus-containing subclass of sphingolipids and are especially important in the nervous tissue of higher animals. A sphingomyelin is formed by the esterification of a phosphorylcholine or a phosphorylethanolamine to the 1-hydroxy group of a ceramide (Figure 8.12).

8.4 ● Sphingolipids

249

FIGURE 8.11 ● Formation of an amide linkage between a fatty acid and sphingosine produces a ceramide.

O

CH3

–O

+

CH3

P

O

CH2CH2

N

OH

H

O

CH3

H

C

C

CH2

H

C

NH

C

H

C

O

Choline sphingomyelin with stearic acid

FIGURE 8.12 ● A structure and a space-filling model of a choline sphingomyelin formed from stearic acid.

FIGURE 8.14

FIGURE 8.13

250 Chapter 8 ● Lipids

CH2OH

β -D-galactose HO

O

H

H

OH

H

H

OH

OH

H

O

H

H

C

C

CH2

C

NH

C

H

C

O

R

A cerebroside

● The structure of a cerebroside. Note the sphingosine backbone.

There is another class of ceramide-based lipids which, like the sphingomyelins, are important components of muscle and nerve membranes in animals. These are the glycosphingolipids, and they consist of a ceramide with one or more sugar residues in a -glycosidic linkage at the 1-hydroxyl moiety. The neutral glycosphingolipids contain only neutral (uncharged) sugar residues. When a single glucose or galactose is bound in this manner, the molecule is a cerebroside (Figure 8.13). Another class of lipids is formed when a sulfate is esterified at the 3-position of the galactose to make a sulfatide. Gangliosides (Figure 8.14) are more complex glycosphingolipids that consist of a ceramide backbone with three or more sugars esterified, one of these being a sialic acid such as N-acetylneuraminic acid. These latter compounds are referred to as acidic glycosphingolipids, and they have a net negative charge at neutral pH.

The glycosphingolipids have a number of important cellular functions, despite the fact that they are present only in small amounts in most membranes. Glycosphingolipids at cell surfaces appear to determine, at least in part, certain elements of tissue and organ specificity. Cell–cell recognition and tissue immunity appear to depend upon specific glycosphingolipids. Gangliosides are present in nerve endings and appear to be important in nerve impulse transmission. A number of genetically transmitted diseases involve the accumulation of specific glycosphingolipids due to an absence of the enzymes needed for their degradation. Such is the case for ganglioside GM2 in the brains of Tay-Sachs disease victims, a rare but fatal disease characterized by a red spot on the retina, gradual blindness, and loss of weight, especially in infants and children.

GM1

GM2

GM3

N-Acetyl-

D-Galactose

D-galactosamine

D-Galactose

D-Glucose

CH2OH

CH2OH

CH2OH

CH2OH

HO

O

HO

O

O

O

H

O

H

H

H

O

H

OH

H

H

H

H

H

H

H

H

H

H

H

H

OH

O

H

NH

H OH

H

OH

O

OH

H

O

C

O

CH3

H

O

H

C

C

CH2

H

O

COO–

H

CH3

C

N

CHOH

C

NH

CHOH

C

H

C

O

CH2OH

H

H

H

R

OH

H

N-Acetylneuraminidate

(sialic acid)

Gangliosides GM1,GM2, and GM3

● The structures of several important gangliosides. Also shown is a spacefilling model of ganglioside GM1.